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Metformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice

Abstract

Insulin deficiency or resistance can promote dementia and hallmarks of Alzheimer's disease (AD). The formation of neurofibrillary tangles of p-TAU protein, extracellular Aβ plaques, and neuronal loss is related to the switching off insulin signaling in cognition brain areas. Metformin is a biguanide antihyperglycemic drug used worldwide for the treatment of type 2 diabetes. Some studies have demonstrated that metformin exerts neuroprotective, anti-inflammatory, anti-oxidant, and nootropic effects. This study aimed to evaluate metformin's effects on long-term memory and p-Tau and amyloid β modulation, which are hallmarks of AD in diabetic mice. Swiss Webster mice were distributed in the following experimental groups: control; treated with streptozotocin (STZ) that is an agent toxic to the insulin-producing beta cells; STZ + metformin 200 mg/kg (M200). STZ mice showed significant augmentation of time spent to reach the target box in the Barnes maze, while M200 mice showed a significant time reduction. Moreover, the M200 group showed reduced GFAP immunoreactivity in hippocampal dentate gyrus and CA1 compared with the STZ group. STZ mice showed high p-Tau levels, reduced p-CREB, and accumulation of β-amyloid (Aβ) plaque in hippocampal areas and corpus callosum. In contrast, all these changes were reversed in the M200 group. Protein expressions of p-Tau, p-ERK, pGSK3, iNOS, nNOS, PARP, Cytochrome c, caspase 3, and GluN2A were increased in the parietal cortex of STZ mice and significantly counteracted in M200 mice. Moreover, M200 mice also showed significantly high levels of eNOS, AMPK, and p-AKT expression. In conclusion, metformin improved spatial memory in diabetic mice, which can be associated with reducing p-Tau and β-amyloid (Aβ) plaque load and inhibition of neuronal death.

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Funding

The authors would like to thank the following Brazilian foundations for financial support: Oswaldo Cruz Foundation of Pernambuco (FIOCRUZ-PE), the Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM; # 465489/2014–1), and National Council for Scientific and Technological Development (CNPq;#301777/2012–8) for research support. This study was financed in part by the Coordination of Improvement of Higher Education Personnel—Brazil (CAPES), and Foundation of Support to Science and Technology of State of Pernambuco (FACEPE; #AMD-0180–2.00/16).

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Correspondence to Christina Alves Peixoto.

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This article is part of the doctoral thesis of Wilma Helena Oliveira, a student at the Federal University of Pernambuco – UFPE.

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Oliveira, W.H., Braga, C.F., Lós, D.B. et al. Metformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice. Exp Brain Res 239, 2821–2839 (2021). https://doi.org/10.1007/s00221-021-06176-8

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Keywords

  • Insulin
  • Metformin
  • Cognition
  • Streptozotocin
  • Diabetes
  • p-TAU
  • Amyloid β